Ibandronate metal complexes: solution behavior and antiparasitic activity

• Published in: Journal of biological inorganic chemistry 2018-03, Vol.23 (2), p.303-312
• Main Authors: Demoro, Bruno, Rostán, Santiago, Moncada, Mauricio, Li, Zhu-Hong, Docampo, Roberto, Olea Azar, Claudio, Maya, Juan Diego, Torres, Julia, Gambino, Dinorah, Otero, Lucía
• Format: Article
• Language: English
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Animals; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Biochemistry; Biomedical and Life Sciences; Bisphosphonates; Bone diseases; Carbon dioxide; Chagas disease; Chlorocebus aethiops; Cobalt; Geranyltranstransferase - antagonists & inhibitors; Ibandronic acid; Ibandronic Acid - chemistry; Ibandronic Acid - pharmacology; Inorganic chemistry; Life Sciences; Metal ions; Metals - chemistry; Microbiology; Original Paper; Protozoa; Species; Toxicity; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - enzymology; Vero Cells
• ISSN: 0949-8257; 1432-1327
• DOI: 10.1007/s00775-018-1535-y

To face the high costs of developing new drugs, researchers in both industry and academy are looking for ways to repurpose old drugs for new uses. In this sense, bisphosphonates that are clinically used for bone diseases have been studied as agents against Trypanosoma cruzi , causative parasite of Chagas disease. In this work, the development of first row transition metal complexes (M = Co 2+ , Mn 2+ , Ni 2+ ) with the bisphosphonate ibandronate (iba, H 4 iba representing the neutral form) is presented. The in-solution behavior of the systems containing iba and the selected 3d metal ions was studied by potentiometry. Mononuclear complexes [M(H x iba)] (2− x )− ( x  = 0–3) and [M(Hiba) 2 ] 4− together with the formation of the neutral polynuclear species [M 2 iba] and [M 3 (Hiba) 2 ] were detected for all studied systems. In the solid state, complexes of the formula [M 3 (Hiba) 2 (H 2 O) 4 ]·6H 2 O were obtained and characterized. All obtained complexes, forming [M(Hiba)] − species under the conditions of the biological studies, were more active against the amastigote form of T. cruzi than the free iba, showing no toxicity in mammalian Vero cells. In addition, the same complexes were selective inhibitors of the parasitic farnesyl diphosphate synthase (FPPS) enzyme showing poor inhibition of the human one. However, the increase of the anti- T. cruzi activity upon coordination could not be explained neither through the inhibition of Tc FPPS nor through the inhibition of Tc SPPS ( T. cruzi solanesyl-diphosphate synthase). The ability of the obtained metal complexes of catalyzing the generation of free radical species in the parasite could explain the observed anti- T. cruzi activity. Graphical abstract